Table 2 Summary of agents prioritised for repurposing for LBD by the international Delphi panel
Proposed candidate | Suggested mechanisms of action | Summary of evidence | Future work required |
|---|---|---|---|
Ambroxol | -Neuroprotective effects through upregulating GCase | -Reduction of α-synuclein pathology and improved mitochondrial function -Penetrates the CSF and engages the treatment target in humans | -Pharmacokinetics -Better understanding of mechanisms -Phase 2 work needed with CNS or CSF biomarkers to support target engagement |
Nilotinib/bosutinib | -Increases the clearance of α-synuclein, amyloid, hyperphosphorylated tau -Stimulates autophagy -Anti-inflammatory effect -Rescues synaptic dysfunction | -Safe, well tolerated -Increase in dopamine metabolites in the CSF -Reduction of CSF α-synuclein oligomers and hyperphosphorylated tau -Worsening of motor scores | -Await results of ongoing trials -Safety work, especially in older adults and QTc prolongation |
Liraglutide/exenatide | -Decreases astrocyte and microglial activation -Decreases chronic inflammation and lipid peroxidation -Suppresses the apoptosis pathway -Increases autophagy-related protein expression -Reduces free oxygen species | -Improvements in off-medication scores on part 3 of the MDS-UPDRS -Lower rate of PD compared to the use of other antidiabetic drugs | -Phase 2 work needed with CNS or CSF biomarkers to support target engagement in LBD |
Candesartan/telmisartan | -Inhibits the expression of TLR2 and TLR4 -Reverses the activated proinflammatory phenotype of primary microglia -Reduces TNF-α levels | -Improvement of motor deficits in animal models -Reduction in levels of α-synuclein and attenuation of ER stress-triggered neuronal apoptosis -Improvement of cognitive performance in various cohorts | -More preclinical evidence and studies on whether they cross the BBB -Additional epidemiological evidence -Phase 2 trials in LBD |
Metformin | -Prevents α-synuclein phosphorylation and aggregation -Prevents astroglia and microglia activation -Improves cell survival and promotes autophagy | -Reduction of amyloid beta secretion and tau phosphorylation -Improves cognitive performance in animal models. -Improves motor impairments in PD animal models -Improves verbal learning and memory in amnestic MCI. | -Phase 2 research needed with CNS or CSF biomarkers to support target engagement in LBD -Prodromal studies in enriched RBD may have a direct relevance for LBD |
Fasudil | -Promotes the degradation of α-synuclein via autophagy through the JNK 1/Bcl-2/beclin 1 pathway -Dilates cerebral vessels -Inhibits the release of intracellular calcium | -Reduction of phosphorylated α-synuclein -Improves motor deficits in various animal models of PD -Rescues cognitive deficits, reduced acetylcholinesterase activity and oxidative stress in AD animal models | -Need clinical/pharmacokinetic studies to CNS penetration -Phase 1 clinical studies |